Effects of antiepileptic drugs in a new TSC/mTOR-dependent epilepsy mouse model

Autor: Martina Proietti Onori, Ilse Wallaard, Annabel van Oort, Nathalie H. R. M. Kooijman, Ype Elgersma, Saskia E. van Grondelle, Linda M. C. Koene, Jadwiga Schreiber
Přispěvatelé: Neurosciences
Rok vydání: 2019
Předmět:
0301 basic medicine
Morpholines
medicine.medical_treatment
Neurosciences. Biological psychiatry. Neuropsychiatry
mTORC1
Mechanistic Target of Rapamycin Complex 1
Lamotrigine
Pharmacology
Epileptogenesis
Tuberous Sclerosis Complex 1 Protein
Vigabatrin
Mice
03 medical and health sciences
Epilepsy
0302 clinical medicine
Tuberous Sclerosis
medicine
Animals
RC346-429
Research Articles
PI3K/AKT/mTOR pathway
Mice
Knockout
Sirolimus
business.industry
TOR Serine-Threonine Kinases
Tumor Suppressor Proteins
General Neuroscience
Brain
medicine.disease
Mice
Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Anticonvulsants
Female
Ras Homolog Enriched in Brain Protein
Neurology (clinical)
TSC1
Neurology. Diseases of the nervous system
Diet
Ketogenic
business
030217 neurology & neurosurgery
Research Article
Ketogenic diet
medicine.drug
RC321-571
Zdroj: Annals of Clinical and Translational Neurology, 6(7), 1273-1291. John Wiley & Sons Inc.
Annals of Clinical and Translational Neurology, Vol 6, Iss 7, Pp 1273-1291 (2019)
Annals of Clinical and Translational Neurology
ISSN: 2328-9503
Popis: Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.
Databáze: OpenAIRE
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